In epidermis, the extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase (Erk MAPK) pathway is activated in a majority of spontaneous human squamous cell carcinomas (SCCs) and can combine with G1 escape to directly transform intact human tissue into lethal SCC. Characterizing Erk MAPK pathway function in normal and neoplastic epidermis has been the longstanding focus of AR49737 and remains so in this competing renewal. Efforts in the prior funding cycle achieved the first disruption of the pathway in mammalian tissue, an advance that underscored its importance in homeostasis and oncogenesis. The current proposal focuses on promising pathway regulators and effectors, namely MAPK-interacting proteins (MAPK-IPs) and newly discovered MAPK-controlled long noncoding RNAs (ncRNAs). First, we will extend our recent findings indicating that loss of the IQGAP1 MAPK-IP selectively blocks epidermal neoplasia without disrupting homeostasis in normal epidermal tissue. We will define the functional domains of IQGAP1 required for Erk MAPK-driven epidermal neoplasia. These efforts will help identify potentially important neoplasia-selective interactions of IQGAP1. In parallel, we will also assess the therapeutic potential of IQGAP1 in SCC by depleting IQGAP1 in early neoplastic progression versus in established neoplasia. These studies are designed to elucidate the role of IQGAP1 in Erk MAPK-driven epidermal neoplasia. Second, we will characterize Erk MAPK targets identified during the prior cycle that represent a putative new class of MAPK effectors, namely long ncRNAs within the epidermal differentiation complex (EDC) on chromosome 1q21. We have termed these new ncRNAs, NEDCRs (noncoding EDC RNAs). To identify the functionally important MAPK targets within this group, we will define NEDCR effects on epidermal growth and differentiation. In parallel, we will focus on NEDCR1 as a prototype for the next level of studies because it dominantly controls epidermal differentiation. We will define the role of NEDCR1 in Erk MAPK-driven epidermal neoplasia. These studies are designed to define the basis for Erk MAPK pathway control of epidermal homeostasis and neoplasia by new ncRNA targets of Erk MAPK action. At the end of the proposed funding period, we hope to have defined the mechanistic basis for the selective requirement for the IQGAP1 MAPK-IP in epidermal neoplasia but not homeostasis and to have characterized the role of a newly discovered class of Erk MAPK effectors, namely long ncRNAs, in the regulation of epidermal homeostasis and cancer.